Abstract
Unintended outcomes of cancer therapy include ionizing radiation (IR)-induced stem cell depletion, diminished regenerative capacity, and accelerated aging. Stem cells exhibit attenuated DNA damage response (DDR) and are hypersensitive to IR, as compared to differentiated non-stem cells. We performed genomic discovery research to compare stem cells to differentiated cells, which revealed Phosphoprotein phosphatase 2A (PP2A) as a potential contributor to susceptibility in stem cells. PP2A dephosphorylates pATM, γH2AX, pAkt etc. and is believed to play dual role in regulating DDR and apoptosis. Although studied widely in cancer cells, the role of PP2A in normal stem cell radiosensitivity is unknown. Here we demonstrate that constitutively high expression and radiation induction of PP2A in stem cells plays a role in promoting susceptibility to irradiation. Transient inhibition of PP2A markedly restores DNA repair, inhibits apoptosis, and enhances survival of stem cells, without affecting differentiated non-stem and cancer cells. PP2Ai-mediated stem cell radioprotection was demonstrated in murine embryonic, adult neural, intestinal, and hematopoietic stem cells.
Highlights
Ionizing radiation (IR) is a major cancer treatment modality for primary and metastatic cancers, but invariably results in debilitating organ dysfunction such as cognitive impairment[1,2] and learning deficiencies in patients subjected to cranial irradiation[3,4]
Through rigorous statistical short listing and verification analyses, we identified overexpression and substantial radiation induction of the catalytic subunit of phosphoprotein phosphatase 2A (PP2A) selectively in stem cells, which was confirmed by RT-PCR (Supplemental Fig. S1C)
Research findings in recent years suggest that stem cell transplant in addition to the use of anti-inflammatory agents may provide a useful intervention strategy for minimizing the adverse effects of cranial irradiation on central nervous system (CNS) function
Summary
Ionizing radiation (IR) is a major cancer treatment modality for primary and metastatic cancers, but invariably results in debilitating organ dysfunction such as cognitive impairment[1,2] and learning deficiencies in patients subjected to cranial irradiation[3,4]. IR therapy-induced intestinal injury is a common problem in patients with abdominal and pelvic cancers and is associated with a loss of stem cells[5]. IR response of progenitor cells is determined mostly by the intrinsic radiation hypersensitivity and unique molecular/epigenetic regulation of DNA damage response (DDR) and apoptotic response (AR) in stem cells[6,7,8]. All the mechanistic regulation of stem cell radiosensitivity has not been elucidated, the differential expression of several genes in stem cells plays a role in attenuated DDR and heightened AR6. We compared the gene expression of ES and ED cells and found that Phosphoprotein Phosphatase 2A (PP2A) contributes to DDR signaling and is associated with the radiosensitivity observed in normal stem cells. PP2A dephosphorylates Akt at Official journal of the Cell Death Differentiation Association
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